The Double-Protonation of Dihapto-Coordinated Benzene Complexes: An Enabling Strategy for Dearomatization Using Aromatic Nucleophiles

Abstract Friedel Crafts Arylation (the Scholl reaction) is the coupling of two aromatic rings with the aid of a strong Lewis or Bronsted acid. This historically significant C-C bond forming reaction normally leads to aromatic products, often as oligomeric mixtures, dictated by the large stabilization gained upon their rearomatization. In this preliminary communication, we demonstrate how the pre-coordination of benzene by tungsten disrupts the natural course of this reaction sequence, allowing for Friedel-Crafts Arylation without rearomatization or oligomerization . Subsequent addition of a nucleophile to the coupled intermediate leads to functionalized cyclohexenes. The key feature of this reaction is a tungsten complex bound through two carbons, which enables a rarely observed double protonation of the bound benzene, and subsequent coupling to the second arene without the need of precious metal or Lewis acid catalysts.


Introduction
Whereas organic alkenes are widely known to undergo a reaction sequence of protonation followed by nucleophilic addition (i.e., alkene electrophilic addition), such a process is generally not accessible to benzenes, owing to the highly stabilized aromatic ring. However, we recently demonstrated that this reaction sequence was not only possible for a dihapto-coordinated benzene complex (Figure 1), 1, 2 but that the resulting h 2 -diene complex (3) could participate in a second protonation/nucleophilic addition sequence to form the corresponding cis-3,6-disubstituted cyclohexene complex (4). 2 The range of nucleophiles that can be added in this manner includes cyanide, enolates, Grignard reagents, amines, and alkoxides. 2 However, the highly π-basic nature of the tungsten system required to coordinate and activate the benzene ring also stabilizes the h 2 -arenium intermediate (2), thereby diminishing its ability to react with so-called "π-nucleophiles" such as arenes and alkenes. 3 We posited that a different strategy, in which the benzene was rst double-protonated, might be possible. The resulting dicationic species (5), if accessible, would be highly electrophilic, and should be capable of reacting with much milder nucleophiles than its monoprotonated precursor 2. The resulting π-allyl species (e.g., 6-8) would then be positioned to react with a second nucleophile to generate 3,6-disubstitued cyclohexene complexes (e.g., [9][10][11].

Results And Discussion
We initially focused on the parent benzene complex, WTp(NO)(PMe 3 )(η 2 -benzene) (1), which we have previously shown could be protonated by a diphenylammonium salt (pK a ~1) to generate the η 2 -arenium complex 2 (Fig. 1). 1 When the η 2 -arenium species 2 is treated with a CD 2 Cl 2 solution of tri ic acid (HOTf; T = 0°C), the 1 H NMR spectrum reveals that a second protonation occurs on the benzene ring to form 5: NOESY and HSQC NMR data indicate two adjacent diastereotopic methylene groups (Fig. 1). Repeating the reaction in neat DOTf at -60°C and gradually warming the solution to 0°C indicates that the initial reaction of 2 and acid generates a paramagnetic complex as indicated by three broad peaks from 7-8.5 ppm. These signals gradually give way to the doubly protonated complex 5 -d 2 as the brown solution turns deep orange. In contrast, if the benzene complex 1 is subjected to HOTf in CD 2 Cl 2 at -30 C, only the monoprotonated complex 2 is formed; this solution evolves to form 5 only after warming to 0°C. Attempts to isolate the dicationic complex 5 by precipitation with ether resulted in decomposition. However, when 5 was generated in situ and treated with anisole, phenol, or thiophene at -30°C, an electrophilic aromatic substitution (EAS) reaction occurred between the free aromatic and the "carbenium" of 5 proximal to the PMe 3 . Addition of the arene occurred anti to the metal to form η 2 -allyl complexes 6-8D. This reactivity signi cantly differs from the precursor η 2 -benzenium complex 2, which shows no signs of reactivity with aromatic compounds, save for indole. 2 The resulting η 2 -allyl species (also referred to as hyperdistorted η 3 -allyl, 4 or σ-π distorted 5-7 ), are heavily weighted toward the conformer with the carbenium carbon distal to the PMe 3 . 4 Subsequently, the addition of a second nucleophile (CN − ) 2, 4 resulted in cis-3,6disubstituted cyclohexene complexes 9-11D. Unfortunately, these products were all accompanied by roughly 20% of a second isomer, both for the η 2 -allyl intermediate (6-8P) and for the nal cyclohexene complex (9-11P). These minor products were ultimately characterized (vide infra) as diastereomers of the major cyclohexene products in which the free arene added to the carbenium distal to the PMe 3 , and the second nucleophile added to the proximal allyl carbon. Attempts to raise the diastereoselectivity of this reaction through adjusting temperature, solvent or reaction time failed to signi cantly improve it.
When the reaction sequence to generate the anisole addition product 9D was repeated using the deuterated benzene complex 1-d 6 , the two protons incorporated in the double protonation sequence were identi ed by two signals appearing for 6D-d 6 at 3.50 and 1. DFT calculations support the notion that the rst protonation of the benzene ring occurs syn to the tungsten via the nitrosonium ligand, where a modest transition state energy of 8.3 kcal/mol is found for proton transfer from the NO oxygen to the ring carbon (red, Fig. 2; SI). Calculations further indicate that an analogous NO-assisted second protonation is also viable (~ 7 kcal/mol), provided that protonation of the nitrosonium of 2 can still occur. However, given that the double protonation of 1-d 6 to form 6D-d 6 unambiguously results in a trans arrangement of the two ring protons, the second protonation must occur by an intermolecular pathway, anti to the metal. Most likely the comparatively lower transition state energy for direct ring protonation (blue dash in Fig. 2) re ects the considerable thermodynamic preference for 5 over the NO-protonated derivative of 2 (2H; -14.2 kcal/mol; Fig. 2).
According to calculations, the double-protonated benzene complex 5 can be considered as a highly distorted η 4 -tungsten(II)-diene complex (Fig. 3), with elongated bond lengths (2.66, 2.79 Å; cf. 2.30, 2.37 Å) between tungsten and the terminal diene carbons. These distorted structural features are reminiscent of those seen for the η 2 -allyl species described earlier. A search of the Cambridge Structural Database 8 failed to identify any analogously distorted η 4 -diene structures; however the structure of 5 is reminiscent to those found in zirconium and hafnium complexes of η 4 -cyclooctatetrene. 9 The distal carbenium carbon of 5 has the longest bond to the metal (2.79 Å) and might be predicted to be the more reactive site of addition, yet, nucleophilic attack occurs predominantly at the proximal carbenium. Such an addition generates η 2 -allyl species (6-8D) with the remaining carbenium distal to PMe 3 . The distal form (D) is known to be several kcal/mol more stable than the isomers resulting from distal addition of the arene (6-8P). 2 Hence, we rationalize the kinetic preference for the addition of the arene to the proximal carbenium by invoking a transition state that resembles the product in which the carbenium is distal to the PMe 3 .
The observed 4:1 selectivity discouraged us from developing a synthetic method for enantioenriched cyclohexenes using this approach. Hints of analogous reactivity were observed for the molybdenum complex MoTp(NO)(DMAP)(η 2 -benzene), 10 (1-Mo) including spectroscopic evidence for the Mo analog of 6D (6D-Mo). The large-scale preparation of 1-Mo and spectroscopic data for 6D-Mo can be found in the SI. However, the high sensitivity of these compounds to acid ultimately discouraged our further investigation.
We next considered a modi ed strategy (Fig. 4) in which an η 2 -anisole complex would be doubleprotonated. We reasoned that the methoxy substituent would not only facilitate the double protonation, but also could help direct the aryl addition to the paracarbon of the anisole, analogous to what we have previously observed for anilines. 11 In contrast to our aniline observations, we anticipated that the oxocarbenium could be easily reduced later in the reaction sequence. The tungsten anisole complex 12D exists in solution as a 3:1 equilibrium with its stereoisomer 12P. 12,13 However, the 2H-anisolium complex 13D has been shown to be thermodynamically favored over its proximal analog 13P (> 20 : 1), again favoring the oxocarbenium carbon in the distal position. 13 When 13D was subjected to highly acidic conditions (HOTf/acetonitrile), protonation occurred exclusively at the homoallylic carbon to form the dication 14D (Fig. 4). Treating this species with the phenol, anisole, and thiophene series resulted exclusively in the enonium species 15-17D.
In the reaction sequences outlined in Fig. 4, a single regio-and stereoisomer of a cis-3,6-disubstituted cyclohexene complex is obtained (9)(10)(11). The synthesis of 3,6-disubstituted cyclohexenes such as 21-23 (derived from 9-11) have not been reported previously, despite their relatively simple structures. The closest comparisons are 1,4-dihydronapthalene analogs prepared from a Diels-Alder reaction with benzyne, 17 or reaction sequences involving the coupling of aryl halides to cyclohexenes or cyclohexanones. More generally, methods employed to couple aromatics to cycloalkanes typically involve cross-coupling reactions such as Negishi, 18 Stille, 19 Suzuki, 20 and Hiyama couplings, 21  intermediate. 25 The closest comparisons of EAS reactions related to the current study involve cyclohexadienyliumiron complexes combining with anilines or phenols to generate carbazoles. 26,27 In these studies, the iron complex does not control the stereochemistry of the reaction and cyclohexadienes or arenes are produced. Limited examples of EAS reactions have also appeared in our own work, in the synthesis of γ-substituted enones. 28 and tetrahydroindolines. 29 However, in no case previously were we able to couple these reactions to a second nucleophilic addition. The full scope of cis-3,6-disubstituted cyclohexenes available by this new method, including enantioenriched variations, will be disclosed in due course.

Declarations
Notes: The authors declare no competing nancial interest.

ACKNOWLEDGMENTS:
Research reported in this publication was supported by the NIGMS of the National Institutes of Health under award number R01GM132205 (80%) and the University of Virginia (20%). Single crystal X-ray diffraction experiments were performed on a diffractometer at the University of Virginia funded by the NSF-MRI program (CHE-2018870). The content is solely the responsibility of the authors and does not necessarily represent the o cial views of the National Institutes of Health or the University of Virginia.